EP0458079A2 - Agent de contraste ultrasonique, sa préparation et application comme diagnostic ou thérapeutique - Google Patents

Agent de contraste ultrasonique, sa préparation et application comme diagnostic ou thérapeutique Download PDF

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Publication number
EP0458079A2
EP0458079A2 EP91106660A EP91106660A EP0458079A2 EP 0458079 A2 EP0458079 A2 EP 0458079A2 EP 91106660 A EP91106660 A EP 91106660A EP 91106660 A EP91106660 A EP 91106660A EP 0458079 A2 EP0458079 A2 EP 0458079A2
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EP
European Patent Office
Prior art keywords
ultrasound contrast
contrast medium
formula
acid
medium according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP91106660A
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German (de)
English (en)
Other versions
EP0458079B1 (fr
EP0458079A3 (en
Inventor
Raimund Prof. Dr. Erbel
Rainer Dr. Zotz
Volker Dr. Krone
Michael Dr. Magerstädt
Axel Dr. Walch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DR F KOEHLER CHEMIE GmbH
Original Assignee
Hoechst AG
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Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
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Publication of EP0458079A3 publication Critical patent/EP0458079A3/de
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Publication of EP0458079B1 publication Critical patent/EP0458079B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to ultrasound contrast media consisting of microparticles which contain a gas and polyaminodicarboxylic acid co-imide derivatives, processes for their preparation and their use as diagnostics and therapeutics.
  • Ultrasonic waves are reflected at interfaces from different types of tissue.
  • the resulting echo signals are electronically amplified and made visible.
  • the visualization of blood vessels and internal organs using ultrasound generally does not allow the visualization of the blood flow contained therein.
  • Liquids, especially blood only provide ultrasound contrast if there are differences in density to the environment.
  • As a contrast medium in medical ultrasound diagnostics e.g. Gas-containing or gas-producing substances are used, since the impedance difference between gas and surrounding blood is much larger than that between liquids or solid bodies and blood (Levine RA, J Am Coll Cardiol 3: 28, 1989; Machi IJ CU 11: 3, 1983 ).
  • EP-A2-0 123 235 and 0 122 624 describe ultrasound contrast agents containing gases, which consist of mixtures of surface-active substances with a solid in a liquid carrier.
  • the ultrasound contrast media are produced by an elaborate grinding process using an air jet mill. The particles produced in this way only have a short service life because they quickly lose the enclosed gases.
  • EP-A2-0 224 934 describes ultrasound contrast media in the form of gas-filled gelatin or albumin hollow bodies.
  • the use of foreign or denatured endogenous proteins is disadvantageous because of the associated allergenic risk.
  • EP-A1-0 327 490 describes microparticles consisting of amyloses or synthetic, biodegradable polymers and a gas and / or a liquid with a boiling point of less than 60 ° C. Disadvantages of these polymers are their sticky consistency in water or blood, their poor biodegradability, their toxicity or the formation of toxic degradation products.
  • the object of the present invention was to develop ultrasound contrast media based on microparticles which provide a clear contrast to the surrounding tissue, which are so small and stable that they reach the left half of the heart after intravenous application without substantial gas loss and essentially quantitatively, have good compatibility without allergenic potential, do not clump together in water or blood and can be produced quickly and easily.
  • Microparticles were produced from polyaminodicarboxylic acid co-imide derivatives (polydicarboxylic acid co-AHADS derivatives), which are surprisingly suitable as ultrasound contrast agents. Due to the incorporation of unopened imide rings (AHADS rings), the suspendability of the microparticles produced is particularly excellent in water. The microparticles do not have a sticky, greasy consistency in water-containing liquids and hardly collect together. The polymers form a pharmacologically inert matrix in which the gas is enclosed. These polymers are metabolized and excreted in vivo to non-toxic, non-allergenic and non-immunogenic compounds.
  • the ultrasound contrast agents according to the invention bring about an improved increase in echogenicity in myocardium and allow an improved endocardium display.
  • the following parameters can also be better assessed, for example: Chamber size, wall movement disorders, stroke volume, ejection fraction or intracavitary masses, eg thrombi or tumors.
  • the ultrasound contrast agents according to the invention enable the evaluation of flow patterns in the case of valve insufficiency of the left and right half of the heart, intracardiac shunts, and the improved display of the large vessels in the case of congenital malformations. A massive amplification of the Doppler signal was also observed.
  • Aryl is understood to mean aromatic hydrocarbons such as phenyl and naphthyl, especially phenyl.
  • the aryl radicals are preferably mono- or disubstituted.
  • the alkyl and alkenyl radicals mentioned can be either straight-chain or branched.
  • the biologically inactive steroid alcohols are preferably bound via their OH group.
  • a preferred steroid alcohol is cholesterol.
  • the amino acids mentioned for R 1 are preferably naturally occurring amino acids such as Tyr, Ala, Ser or Cys, particularly preferably Tyr and Ala. They can be bound via their NH2 as well as their COOH function.
  • the invention also relates to processes for the production of gas-containing microparticles which consist of or contain the abovementioned polymers and their use, also in admixture with other, biocompatible and / or biodegradable polymers or physiologically acceptable auxiliaries, for diagnostic or therapeutic processes.
  • Another object of the invention are diagnostic or therapeutic agents, consisting of at least one of the above-mentioned contrast agents.
  • the invention also relates to processes for the production of diagnostic or therapeutic agents, which are characterized in that the above-mentioned ultrasound contrast agents are brought into a suitable dosage form with a physiological carrier and, if appropriate, further additives and / or auxiliary substances.
  • Aspartic acid and / or glutamic acid are used as aminodicarboxylic acids, which react in a polycondensation reaction to give the corresponding polyimides (polyanhydroaminodicarboxylic acids, formula II).
  • polyimides polyanhydroaminodicarboxylic acids, formula II.
  • m and R 1 are as defined above for formula I, an ⁇ , ⁇ -poly-D, L-amino acid ester co-imide of the formula VIII is obtained
  • polyanhydroaminodicarboxylic acid (II) is only partially converted into the open-chain derivatives.
  • the proportion of unopened anhydroaminodicarboxylic acid units is 0.1 to 99.9%, preferably 10 to 90% (the percentages relate to the total number of repeat units in the total polymer).
  • ⁇ - or ⁇ -linked amino acids are obtained.
  • Compounds of the formulas III and IV which are preferably used are: 2-aminoethanol, 3-aminopropanol, 2-aminopropanol, alcohols having 1 to 18 carbon atoms, in particular methanol, ethanol, isoamyl alcohol and isopropyl alcohol.
  • a general working procedure for the production of PHEA can be found in P. Neri, G. Antoni, Macromol. Synth. Vol. 8, 25. This reference is expressly referred to here.
  • the conversion takes place in high yield to a product with a high degree of purity.
  • the protective group is split off either by adding an HCl / HBr mixture to the free poly- ⁇ -L-glutamic acid or in the presence of hydroxyalkylamines to the analogous poly- ⁇ - (hydroxyalkyl) -L-glutamines.
  • a general working procedure for the production of poly- ⁇ - (hydroxypropyl) -L-glutamine can be found in US Pat. No. 4,356,166, to which reference is expressly made here.
  • glutamic acid can be incorporated up to high proportions in the simple condensation of aspartic acid by means of phosphoric acid to polyanhydroaspartic acid-co-glutamic acid.
  • X stands for a leaving group, which enables a gentle esterification of the polymer alcohol group. Chlorine, bromine, iodine, imidazolides, anhydrides or hydroxyl, in particular chlorine, are preferred.
  • reaction with the compounds of the formula type V, VI or VII can be carried out with a single such compound take place as well as with any combination of these compounds or with compounds which have different, for example in the nature of their branching, especially in their chain length, different radicals R1.
  • the unicorn variant of Schotten-Baumann acylation in the presence of pyridine is particularly suitable. Under gentle conditions, very high degrees of derivatization (greater than 70%) are achieved.
  • the molecular weight of the polymers is 200 to 100,000, preferably 3,000 to 70,000.
  • the chloroformic acid esters (formula VII) are obtained by reacting phosgene with the corresponding biologically inactive, physiologically acceptable, aromatic, araliphatic, aliphatic or cycloaliphatic, in particular unbranched alcohols. Alcohols which have an even number of carbon atoms are particularly preferably used.
  • the chloroformylated steroids are also obtained in this way. In principle, all biologically inactive steroids with reactive hydroxyl groups are accessible. Examples include: cholesterol, cholestanol, coprostanol, ergosterol, sitosterol or stigmasterol.
  • the acid chlorides (formula VI) which can also be used are obtained, for example, from the corresponding carboxylic acids by reaction with phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
  • An advantageous method for producing the ultrasound contrast agents is to dissolve one or more of the polyaminodicarboxylic acid co-imide derivatives of the formula I in a solvent or solvent mixture with a high melting point, or to dissolve these derivatives with one or more other polymers and / or physiologically acceptable Mix excipients and dissolve in a solvent or solvent mixture with a high melting point and in a condensed cold gas, for. B. liquid nitrogen to drip.
  • the Leidenfrost phenomenon creates absolutely round particles.
  • solvents which can be used are alcohols, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane, acetonitrile or mixtures with alcohols.
  • the high-melting and water-miscible solvent is, for. B. dissolved by transferring the microparticles in water and the polymer precipitated thereby, the spherical shape of the microparticles is retained.
  • the organic solvent used has not only a high melting point but also a low boiling point
  • this dropletization process can be further simplified by the solvent, for example tert. Butanol, can be gently removed directly using freeze drying.
  • Another method for producing the ultrasound contrast agents is to dissolve one or more of the polyaminodicarboxylic acid co-imide derivatives of the formula I in a solvent or solvent mixture and, if appropriate, to precipitate them after adding another solvent and / or one or more other polymers or in To disperse water.
  • suitable polymers are, for example, polyvinyl alcohol ( ® Mowiol 28-99) or polyoxyethylene polyoxypropylene ( ® Pluronic F 127).
  • As another solvent such. B. ether can be used. Microparticles with a diameter of 0.5 to 15 microns are obtained by vigorous stirring, for. B. with a mixer (25000 rpm). The solvents are then z. B. removed by lyophilization.
  • a particularly advantageous method is to obtain the microparticles by spray drying.
  • one or more polyaminodicarboxylic acid co-imide derivatives of the formula I are dissolved or these derivatives are mixed with one or more other polymers and / or physiologically acceptable auxiliaries and brought into solution.
  • suitable solvents or solvent mixtures are alcohol, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane or acetonitrile.
  • the solution is then sprayed into microparticles in a spray dryer.
  • the polymers of the formula I can be used alone or as a mixture of different polymers of the formula I. These polymers can also be used in mixtures with other biodegradable and / or biocompatible polymers (e.g. ® Pluronic F68, PHEA, dextrans, polyethylene glycols, hydroxyethyl starch and other degradable or excretable polysaccharides) or physiologically acceptable additives (e.g. polymer plasticizers).
  • biodegradable and / or biocompatible polymers e.g. ® Pluronic F68, PHEA, dextrans, polyethylene glycols, hydroxyethyl starch and other degradable or excretable polysaccharides
  • physiologically acceptable additives e.g. polymer plasticizers
  • the microparticles contain gas, for example air, nitrogen, noble gases such as helium, neon, argon or krypton, hydrogen, carbon dioxide, oxygen, or mixtures thereof.
  • gas for example air, nitrogen, noble gases such as helium, neon, argon or krypton, hydrogen, carbon dioxide, oxygen, or mixtures thereof.
  • the microparticles are loaded with a gas, for example by storing the microparticles in an appropriate gas atmosphere after the lyophilization or by spray drying directly during production in an appropriate gas atmosphere.
  • the ultrasound contrast agents according to the invention are converted into a suitable diagnostic or therapeutic administration form by adding one or more physiologically acceptable carriers and, if appropriate, further additives and / or auxiliaries.
  • the ultrasound contrast media are suspended, for example, by adding water and mixing before application.
  • the physiological isotonicity of the particle suspension can be produced by adding osmotically active substances, for example table salt, galactose, glucose, fructose.
  • osmotically active substances for example table salt, galactose, glucose, fructose.
  • particle sizes can be achieved in which 90% of the particles are between 0.1 ⁇ m and 15 ⁇ m.
  • the spray drying process can be used to achieve particle size distributions in which 90% of the particles are smaller than Are 3 ⁇ m. Larger particles are removed by sieving, for example using a 15 ⁇ m sieve cloth and / or 3 ⁇ m sieve cloth.
  • particle sizes from 0.1 ⁇ m to 7 ⁇ m have proven successful, particle sizes from 0.1 ⁇ m to 3 ⁇ m are advantageously used.
  • the ultrasound contrast agents are injected into the bloodstream, for example. 0.1 mg to 1000 mg of the microparticles, preferably 1 mg to 100 mg, are used per injection.
  • the ultrasound contrast agents described above can be used for both diagnostic and therapeutic methods.
  • the use of the ultrasound contrast agents according to the invention is not only limited to the visualization of the blood flow in the right ventricular part of the blood circulation after venous application.
  • the ultrasound contrast agents can be used with excellent success for the examination of the left side of the heart and the myocardium. It is also possible to visualize other organs supplied with blood, such as the liver, spleen, kidney or brain, with these contrast media.
  • the ultrasound contrast agents according to the invention are also suitable for making cavities in humans, animals or plants visible, for example urinary bladder, ureter, uterus or vagina.
  • DMF dry N, N-dimethylformamide
  • the precipitated product is filtered off, washed with ether, acetone, water, acetone and ether. About 8 g of a white polymer with a degree of substitution of approximately 100% are obtained (can be checked by NMR spectroscopy).
  • the resulting polymer is e.g. B. in acetonitrile with a trace of dimethyl sulfoxide (DMSO), soluble in DMSO or DMF.
  • DMSO dimethyl sulfoxide
  • the contents are placed in a beaker with 200 ml of water and stirred for 30 minutes (200 rpm).
  • the supernatant water is decanted off and the microparticles are lyophilized (diameter after lyophilization: 0.5 to 15 ⁇ m).
  • microparticles are transferred to 200 ml of water and extracted from residual solvent for 2 hours. Excess water is decanted off and the microparticles are lyophilized (diameter after lyophilization: 1-2 ⁇ m).
  • the size distribution of the microparticles was determined in a Cilas 715 granulometer.
  • suspension aids consist of 150 mg Dextran 40 (company Roth, W.-Germany), 7.5 mg polysorbate and 13.5 mg NaCl in 1.5 ml distilled water.
  • the suspensions are filtered with sieve fabrics (15 ⁇ m and 3 ⁇ m mesh size) and then lyophilized. Before application, the microparticles are suspended with water.
  • the left half of the heart After passing through the lungs, the left half of the heart can be recognized by the contrast medium.
  • the ultrasound contrast before and after the lung passage is of the same intensity, so that one can assume that the air remains essentially completely in the polymers and that the microparticles are transported to the left half of the heart essentially without loss.

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  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Physics & Mathematics (AREA)
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  • Acoustics & Sound (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)
EP91106660A 1990-04-26 1991-04-25 Agent de contraste ultrasonique, sa préparation et application comme diagnostic ou thérapeutique Expired - Lifetime EP0458079B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4013231 1990-04-26
DE4013231 1990-04-26

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EP0458079A2 true EP0458079A2 (fr) 1991-11-27
EP0458079A3 EP0458079A3 (en) 1992-01-02
EP0458079B1 EP0458079B1 (fr) 1994-07-20

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US (1) US5137928A (fr)
EP (1) EP0458079B1 (fr)
JP (1) JP3381930B2 (fr)
AT (1) ATE108666T1 (fr)
CA (1) CA2041260C (fr)
DE (1) DE59102225D1 (fr)
DK (1) DK0458079T3 (fr)
ES (1) ES2058978T3 (fr)
IE (1) IE65065B1 (fr)

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US5957848A (en) * 1992-10-10 1999-09-28 Andaris Limited Preparation of further diagnostic agents
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WO2018109201A1 (fr) 2016-12-16 2018-06-21 Basf Se Films multicouche à action détergente et nettoyante, procédé de production desdits films et utilisation correspondante
WO2018109200A1 (fr) 2016-12-16 2018-06-21 Basf Se Feuilles multicouches, leur procédé de fabrication et leur utilisation
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WO2019238761A1 (fr) 2018-06-15 2019-12-19 Basf Se Films multicouches hydrosolubles contenant des produits chimiques et des enzymes actifs de lavage
WO2019238730A1 (fr) 2018-06-14 2019-12-19 Basf Se Procédé pour la production de contenants hydrosolubles pour l'ajout dosé de détergent
WO2020035567A1 (fr) 2018-08-16 2020-02-20 Basf Se Films polymères hydrosolubles d'homopolymères ou de copolymères d'oxyde d'éthylène, procédé de calandrage pour leur production et leur utilisation
WO2020224962A1 (fr) 2019-05-03 2020-11-12 Basf Se Films hydrosolubles à topographie tridimensionnelle
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WO2018109201A1 (fr) 2016-12-16 2018-06-21 Basf Se Films multicouche à action détergente et nettoyante, procédé de production desdits films et utilisation correspondante
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JPH04225926A (ja) 1992-08-14
DE59102225D1 (de) 1994-08-25
IE65065B1 (en) 1995-10-04
DK0458079T3 (da) 1994-11-21
EP0458079B1 (fr) 1994-07-20
ES2058978T3 (es) 1994-11-01
IE911385A1 (en) 1991-11-06
ATE108666T1 (de) 1994-08-15
CA2041260C (fr) 2002-01-01
EP0458079A3 (en) 1992-01-02
CA2041260A1 (fr) 1991-10-27
US5137928A (en) 1992-08-11
JP3381930B2 (ja) 2003-03-04

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